Hyaluronic acid modified extracellular vesicles targeting hepatic stellate cells to attenuate hepatic fibrosis.

RATIONALE: Transforming growth factor-beta1 (TGF-ß1) plays a pivotal role in promoting hepatic fibrosis, pirfenidone (PFD) could inhibit TGF-ß1 signaling pathway to alleviate hepatic stellate cells (HSC) activation mediated hepatic fibrosis. The targeting delivery strategy of PFD to hepatic stellate cells is a challenge. Extracellular vesicles (EVs), cell-derived membranous particles are intraluminal nano-vesicles that play a vital role in intercellular communication, they also be considered as an ideal nano-carrier. METHODS: In this study, we developed a target strategy to deliver PFD to HSC with CD44 over-expression by EVs, hyaluronic acid (HA) modified DSPE-PEG2000 endows the active targeting ability of activated HSCs to PFD-loaded EVs. RESULTS: In both rat hepatic stellate cell line HSC-T6 and rat hepatocyte cell line BRL, HA@EVs-PFD demonstrated the capacity to down-regulate the expression of collagen-synthesis-related proteins and showed superior inhibition efficacy of HSC-T6 activation compared to free PFD. In hepatic fibrosis model, 4 weeks of HA@EVs-PFD treatment resulted in a reduction in liver collagen fibers, significant improvement in hepatic cell morphology, and amelioration of hepatic fibrosis. CONCLUSIONS: HA@EVs-PFD, as a drug delivery system that effectively targets and inhibits activated HSCs to treat hepatic fibrosis, holds promise as a potential therapeutic agent against hepatic fibrosis.

Oral liposomes encapsulating ginsenoside compound K for rheumatoid arthritis therapy.

Ginsenoside compound K (GCK) can efficiently treat rheumatoid arthritis (RA) due to its immune and anti-inflammatory functions. However, GCK exists some shortcomings such as poor aqueous solubility, low permeability to the intestinal cell membrane, and serious P-gp efflux, thus limiting its application. In order to solve these problems, a folic acid-targeted drug delivery system based on liposomes (FA-LP-GCK) was developed. The prepared FA-LP-GCK had a uniform size distribution and spherical structure, the particle size was 249.13 ± 1.40 nm. Meanwhile, they had high encapsulation efficiency (93.33 ± 0.05 %). FA-LP-GCK also presented good stability in artificial gastric juice, so they can be absorbed into the intestine and enter the blood circulation. The activated RAW 264.7 cells were chosen to evaluate the cytotoxicity and cellular uptake capacity of FA-LP-GCK. FA-LP-GCK showed stronger growth inhibition and cellular uptake ability against activated macrophages. Finally, the efficacy of FA-LP-GCK in vivo was evaluated in the adjuvant arthritis rat model. The results showed that FA-LP-GCK can significantly reduce joint swelling. Furthermore, it can significantly inhibit the expression of pro-inflammatory cytokines and improve synovial hyperplasia of joints and pathological changes in the spleen. Therefore, FA-LP-GCK may be a potential therapeutic approach for RA.

Potential Drug Prediction of Glioblastoma Based on Drug Perturbation-Induced Gene Expression Signatures.

OBJECTIVES: Glioblastoma (GBM) is a malignant brain tumor which is the most common and aggressive type of central nervous system cancer, with high morbidity and mortality. Despite lots of systematic studies on the molecular mechanism of glioblastoma, the pathogenesis is still unclear, and effective therapies are relatively rare with surgical resection as the frequently therapeutic intervention. Identification of fundamental molecules and gene networks associated with initiation is critical in glioblastoma drug discovery. In this study, an approach for the prediction of potential drug was developed based on perturbation-induced gene expression signatures. METHODS: We first collected RNA-seq data of 12 pairs of glioblastoma samples and adjacent normal samples from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by DESeq2, and coexpression networks were analyzed with weighted gene correlation network analysis (WGCNA). Furthermore, key driver genes were detected based on the differentially expressed genes and potential chemotherapeutic drugs and targeted drugs were found by correlating the gene expression profiles with drug perturbation database. Finally, RNA-seq data of glioblastoma from The Cancer Genome Atlas (TCGA) dataset was collected as an independent validation dataset to verify our findings. RESULTS: We identified 1771 significantly DEGs with 446 upregulated genes and 1325 downregulated genes. A total of 24 key drivers were found in the upregulated gene set, and 81 key drivers were found in the downregulated gene set. We screened the Crowd Extracted Expression of Differential Signatures (CREEDS) database to identify drug perturbations that could reverse the key factors of glioblastoma, and a total of 354 drugs were obtained with p value < 10-10. Finally, 7 drugs that could turn down the expression of upregulated factors and 3 drugs that could reverse the expression of downregulated key factors were selected as potential glioblastoma drugs. In addition, similar results were obtained through the analysis of TCGA as independent dataset. CONCLUSIONS: In this study, we provided a framework of workflow for potential therapeutic drug discovery and predicted 10 potential drugs for glioblastoma therapy.

NO up-regulates migraine-related CGRP via activation of an Akt/GSK-3ß/NF-κB signaling cascade in trigeminal ganglion neurons.

The release of the neuropeptide CGRP from the trigeminal ganglion neurons (TGNs) plays a central role in migraine. Whereas CGRP can activate NO release from ganglionic glial cells, NO in turn enhances CGRP release. However, it remains unclear how NO promotes CGRP release. Here, we report that the NO donor SNAP triggered CGRP release from cultured primary TGNs. This event was associated with GSK-3ß activation and Akt inactivation. Immunofluorescent staining revealed that GSK-3ß primarily located in neurons. Furthermore, GSK-3ß inhibition resulted in a marked reduction in expression of CGRP as well as other migraine-related factors, including substance P, cholecystokinin, and prostaglandin E2. Last, exposure to SNAP also activated NF-κB, while NF-κB inhibition prevented the induction of CGRP by SNAP. Interestingly, this event was blocked by GSK-3ß inhibition, in association with inhibition of NF-κB/p65 expression and nuclear translocation. Together, these findings argue that NO could stimulate TGNs to release of CGRP as well as other migraine-related factors, likely by activating GSK-3ß, providing a novel mechanism underlying a potential feed-forward loop between NO and CGRP in migraine. They also raise a possibility that GSK-3ß might act to trigger migraine through activation of NF-κB, suggesting a link between neuroinflammation and migraine.

Pacemaker implantation for treating migraine-like headache secondary to cardiac arrhythmia: A case report.

RATIONALE: Co-occurrence of headache and arrhythmia is not rare. However, their causal relationship remains unclear. Here, we described a case of migraine-like headache relieving with pacemaker implantation. Our case study indicates that arrhythmia is causal for migraine-like headache, which, to our knowledge, has never been reported. PATIENT CONCERNS: A 63-year-old woman patient suffered from paroxysmal headache with a visual aura presenting like migraine for 2 years. No ophthalmic or neurological disorder was found, but cardiac examination detected bradycardia, which was confirmed by 24-hour dynamic electrocardiogram (DCG) revealing sinus bradycardia mixed with ventricular premature beats and supraventricular tachycardia. Transcranial doppler (TCD) detected an equal echo flat plaque on the anterolateral wall of the common carotid artery (CA) bifurcation. DIAGNOSIS: Migraine-like headaches secondary to arrhythmia. INTERVENTIONS: The patient underwent pacemaker implantation. OUTCOMES: Both visual aura and headache were resolved following pacemaker implantation. LESSONS: To the best of the authors' knowledge, we are the first to report migraine-like headache as a secondary symptom of arrhythmia. Arrhythmia may aggravate insufficient blood supply to the brain due to CA lesion and induce a migraine-like headache. This case study indicated that pacemaker implantation could be a fundamental treatment for migraine-like headaches caused by cardiac arrhythmia.

MoO2 nanosheets embedded in amorphous carbon matrix for sodium-ion batteries.

MoO2 nanosheets embedded in the amorphous carbon matrix (MoO2/C) are successfully synthesized via a facile hydrothermal method and investigated as an anode for sodium-ion batteries. Because of the efficient ion transport channels and good volume change accommodation, MoO2/C delivers a discharge/charge capacity of 367.8/367.0 mAh g-1 with high coulombic efficiency (99.4%) after 100 cycles at a current density of 50 mA g-1.

Dissociative adsorption of 3-chloropropyne on Si(111)-(7 × 7): binding and structure.

To achieve silicon functionalization for the development of hybrid devices, multifunctional molecules may be employed to attach to the silicon surfaces. It is important to get a fundamental understanding about the molecule/silicon interface chemistry and the binding configuration. The surface chemistry of 3-chloropropyne (HC≡C-CH(2)Cl) on the Si(111)-(7 × 7) surface, as a model system for understanding the interaction of the multifunctional molecules with a silicon surface, was studied by X-ray photoelectron spectroscopy (XPS), high-resolution electron energy loss spectroscopy (HREELS), and density functional theory (DFT). The 3-chloropropyne adsorbs molecularly on the silicon surface at 110 K. A chemical reaction clearly occurs such that 3-choloropropyne bonds onto the Si(111)-(7 × 7) surface at room temperature by forming C-Si linkage through the cleavage of C-Cl bond, and preserving the ethyne C≡C triple bond. This functionalized silicon surface may act as an intermediate for the growth of multiple organic layers by further attaching other functional molecules.

Electrical stimuli improve osteogenic differentiation mediated by aniline pentamer and PLGA nanocomposites.

Electrical stimulation may improve the proliferation of animal cells. In the present study, osteoblasts were cultured on electroactive aniline pentamer (AP)/poly(lactic-co-glycolic acid) (PLGA) copolymer composites, on which electric pulse was imposed. The combination of polymer and electric pulse enhanced the osteogenic differentiation of the osteoblasts, characterized by the upregulated expression of bone morphogenetic protein (BMP)-2, collagen I and osteonectin and the phosphorylation of Samd4, in contrast to polymer or electrical pulse alone. This action occurred in a polymer content-dependent manner. Therefore, the action of the electric pulse, assisted by the electroactive polymer implant, may be promising in the expedition of injured bone repair.

A new variant nummular headache: large diameter accompanied with bitrigeminal hyperalgesia and successful treatment with carbamazepine.

Nummular headache (NH) is defined as a focal head pain that is exclusively felt in a small area, which is typically 1-6 cm in diameter. Neurological examinations are normal in all patients, but this report describes a new variant. A patient was identified who presented with focal head pain that was approximately 8 cm in diameter and bitrigeminal hyperalgesia on neurological examination. Treatment with carbamazepine provided significant analgesic relief in terms of both the frequency and intensity of pain. The findings enlarge the clinical diversity of this headache disorder. The pathogenic mechanisms of NH may be similar to trigeminal neuralgia in particular patients.

Rizatriptan benzoate influences the endogenous pain modulatory system in a rat model of migraine.

The present study utilized a nitroglycerin-induced rat model of migraine to detect the effects of rizatriptan benzoate on proenkephalin and substance P gene expression in the midbrain using real-time quantitative polymerase chain reaction and investigate whether rizatriptan benzoate can regulate the endogenous pain modulatory system. The results showed that rizatriptan benzoate significantly reduced expression of the mRNAs for proenkephalin and substance P. Rizatriptan benzoate may inhibit the analgesic effect of the endogenous pain modulatory system.

Influence of evoked HSP70 expression on hearing function of the cochlea in guinea pigs.

OBJECTIVE: To investigate the effect of evoked heat shock protein 70 (HSP70) expression on the hearing function of the cochlea in guinea pigs. METHODS: Guinea pigs were divided into pre-exposure group (pre-treated with white noise exposure at 100 dB SPL for 45 min) and none pre-exposure group. Auditory brainstem response (ABR) thresholds were recorded at 12, 60 and 108 h after the animals in both groups were exposed to loud white noise (125 dB SPL, 90 min). RESULTS: HSP70 expression was evoked by pre-treatment with white noise (100 dB SPL, 45 min). There was no significant difference of ABR thresholds between the 2 groups (P>0.05) at 12 h after exposure to loud noise, while ABR thresholds became lower in pre-exposure group than in none pre-exposure group (P<0.01) at both 60 and 108 h. In the pre-exposure group, ABR thresholds at 108 h were significantly lower than that measured at 60 h (P<0.05), but which was not the case in none pre-exposure group. CONCLUSION: HSP70 expression induced by pre-exposure to noise protects the hearing function of the cochlea in guinea pigs.